Macrophages are central in directing host-biomaterial interaction and many disease etiologies. We hypothesized that biomimetic oligopeptides can be designed from the functional structure of macrophage-active proteins (fibronectin and intedeukin-1) and employed to probe the ligand-receptor interaction and post-ligation events as a basis for seeking a greater understanding in the molecular control mechanism involved in macrophage behavior. Furthermore, these peptides were utilized as a component of a platform technology in the development of novel biomaterials to partly modulate macrophage function in vitro and in vivo. In this resubmission of the competing renewal application, we hypothesize that the observed peptide-mediated macrophage behavior is contributed by the preferential ligand conformation upon surface immobilization and the presence of multiple intracellular events in regulating macrophage function. To address these goals, three interrelated aims are formulated: (1) to determine the peptide conformation upon immobilization onto chemically distinct substrates (TCPS, copolymer of monomethoxy-PEG-monoacrylate-colacrylic acid-co-tetramethylolpropylacrylate, and interpenetrating networks containing chemically modified gelatin and polyethyleneglycol-diacrylate) and to correlate this structure with ligand-integrin recognition and binding, (2) to identify intracellular tyrosine phosphorylated proteins, alternative post-ligation intracellular pathways, post-ligation gene expression and cellular function in peptide-mediated adherent macrophages using mono- and co-culture systems, (3) to quantify and model the binding kinetics of macrophage-active oligopeptides with integrins, and to correlate with the identified phosphorylated integrin-associated proteins upon peptide-integrin complexation. Our continuing effort in probing the molecular mechanism of material-macrophage interaction has shed insights on ligand-receptor association and regulation pathways for phagocytic cell function, that are fundamental in understanding the host-material interrelationship for biomedical devices.